Cell-cell signalling is a fundamental process in pattern development. The Drosophila segment polarity genes encode mediators of cell-cell signalling that function both during embryonic and imaginal development. One of these, wingless, encodes a secreted protein, homologous to the Wnt-1 protooncogene, that functions to determine cell fate in the developing fly. Mutations in the wingless signalling pathway that act during embryogenesis lead to alterations in the pattern of the embryonic segments, while mutations acting later in development affect a variety of adult structures. While the mechanism by which wingless signal transduction occurs is poorly understood, the dishevelled gene appears to play a key role in this process. In addition to mediating the wingless cell-cell signalling pathway, dishevelled is required for generation of the wild type tissue polarity manifested in the pattern of hairs and bristles on the adult cuticle. Control of tissue polarity also appears to involve a cell-cell signalling process. Therefore, dishevelled is important in two developmental pathways requiring cell- cell signalling, and serves as a paradigm for understanding the mechanisms by which cells communicate in developmental processes. In this proposal, I focus on experiments to elucidate the molecular mechanism by which dishevelled transduces intercellular signals in both the wingless and tissue polarity pathways, and to identify other gene products involved in these processes. My long range goals include developing an understanding of normal and abnormal developmental processes and their role in health and disease. I hope to continue in a career involving basic science research in an academic setting, and to maintain an interface with the practice of medicine both as a source for stimulation of research questions, and as a potential outlet for applications arising from the pursuit of those questions. I will be undertaking a postdoctoral fellowship during the course of this granting period in Dr. Norbert Perrimon's laboratory in the Department of Genetics at Harvard Medical School, which provides an ideal intellectual and physical environment in which to undertake these pursuits.
| Axelrod, J D; Miller, J R; Shulman, J M et al. (1998) Differential recruitment of Dishevelled provides signaling specificity in the planar cell polarity and Wingless signaling pathways. Genes Dev 12:2610-22 |
| Klingensmith, J; Yang, Y; Axelrod, J D et al. (1996) Conservation of dishevelled structure and function between flies and mice: isolation and characterization of Dvl2. Mech Dev 58:15-26 |
